Development of a Chemoenzymatic Manufacturing Process for Pregabalin

Abstract

A new manufacturing process for (S)-3-(aminomethyl)-5-methylhexanoic acid (Pregabalin), the active ingredient in Lyrica, has been developed. Using Lipolase, a commercially available lipase, rac-2-carboxyethyl-3-cyano-5-methylhexanoic acid ethyl ester (1) can be resolved to form 2-carboxyethyl-3-cyano-5-methylhexanoic acid (2). A heat-promoted decarboxylation of 2 efficiently generates (S)-3-cyano-5-methylhexanoic acid ethyl ester (3), a known precursor of Pregabalin. This new route dramatically improved process efficiency compared to the first-generation process by setting the stereocenter early in the synthesis and enabling the facile racemization and reuse of (R)-1. The chemoenzymatic process also reduced organic solvent usage resulting in a mostly aqueous process. Compared to the first-generation manufacturing process, the new process resulted in higher yields of pregabalin (40-45% after one recycle of (R)-1), and substantial reductions of waste streams corresponding to a 5-fold decrease in the E factor from 86 to 17.

Biocatalytic Process Design and Reaction Engineering

“…Lipase-catalysed resolution of rac-2-carboxyethyl-3-cyano-5-methyl-hexanoic acid ethyl ester and subsequent decarboxylation has been a key process improvement in the synthesis of the Pregabalin precursor (S)-3-cyano-5-methylhexanoic acid ethyl ester 53 . In the case of the (S)-and (R)-lactaldehydes, the identification of the most suitable ketoreductases has been decisive for the key biocatalytic asymmetric reductions of 1,1-dimethoxy-2-propanone to enantiomerically pure (S)-and (R)-1,1-dimethoxy-2-propanols, which have been obtained in ≥99.9 % ee and excellent yield 33 .…”

Green Chemistry – Aspects for the Knoevenagel Reaction

“…6, synthesis of MDL 103371 (25) involves production of key intermediate (28) in yields of 91.0% via the condensation of 4,6-dichloro-3-formyl-1H-indole-2-carboxylate (26) with 3-nitrophenylacetonitrile (27); this piperidine-catalysed step is carried out using ethanol under reflux conditions for 70 hours (Walker et al, 2011). (29), is a lipophilic GABA (γ-aminobutyric acid) analogue used for the treatment of several central nervous system (CNS) disorders, such as epilepsy, neuropathic pain, anxiety and social phobia (Martinez et al, 2008). As shown in Fig.…”

Enzyme Catalysis in the Synthesis of Active Pharmaceutical Ingredients

“…An efficient enzyme-catalyzed hydrolysis of a diester has recently been developed for a second-generation manufacturing process for S-3-(aminomethyl)-5-methylhexanoic acid 106, Pregabalin, the active ingredient of Lyrica [54]. In the first-generation synthesis of pregabalin 106, the racemic acid was resolved by crystallization of diastereomeric salt at the end of the API synthesis step, providing the desired S-isomer 106 in 25% yield with an ee of 99.5%.…”